Lifting the Veil: A Review of the History, Clinical-Usage and
Safety of LSD, Ibogaine and MDMA in a Psychotherapeutic Context

By Christopher D. Lovett
The University of Arizona
Program in Cognition and Neural Systems

Part IV - MDMA

(The voice of Alexander Shulgin): Janice, her son, and I,
all three of us, took 120 milligrams of MDMA in the early
afternoon, and the son went off by himself. At about the half
hour point, the usual "awareness" time, Janice gave no
indication of effects, nor were there any changes at the 40
minute nor 50 minute point. A few off-hand comments were
offered.

"My throat is dry."

"I'll get you a glass of water." Which I did. It did no
good.

"I'm having trouble breathing."

"So, breathe as best you can." I noticed by the reflection
in the window where we were, at the back of the house, that she
had no difficulty breathing when I wasn't watching her.

We walked up the hill, to an area I had leased out to the
condominium builders on the neighboring land for storage of
lumber. There were several 'no smoking' signs around as fire
warnings.

"Do you think I smoke too much?"

"Do you think you smoke too much?"

"I don't think so."

"Then the answer is: probably not."

It was now an hour into the experiment, and still no
acknowledgment of any activity from the MDMA. Then, came the
unexpected question, the "off the wall" question.

"Is it all right to be alive?"

"You bet your sweet ass it's all right to be alive! It's
grace to be alive!"

That was it. She plunged into the MDMA state, and started
running down the hill, calling out that it was all right to be
alive. All the greens became living greens and all the sticks
and stones became vital sticks and stones. I caught up with her
and her face was radiant. She told me some of her personal
history which she knew well, and which I knew well, but with
which she had never come to peace.

She had come into the world by an unexpected Caesarean
section and her mother had died during the delivery. And for
fifty years she had lived in the guilt of having had her life
given her at the cost of her mother's life. She had been in
therapy with her family physician for about three years,
largely addressing this problem, and apparently what she
needed was the acknowledgment that it was all right to be alive.

I didn't hear from her for a couple of months. When she
did call, she volunteered that she still felt very much at
peace, and had discontinued her therapy.
[from Shulgin & Shulgin, 1992: pp. 71-72]

3,4-Methylenedioxymethamphetamine (MDMA) is yet another
compound with a long and circuitous history as a
psychotherapeutic adjunct. MDMA is the N-methylated congener of
3,4-methylenedioxyamphetamine (MDA), a popular street-drug and
psychotherapeutic agent of the late 1960s. MDA, also known as
the "Hug Drug" or "Mellow Drug of America" within the 1960s
counter-culture, has been described as enhancing feelings of
well-being, empathy, insight and self-awareness while decreasing
levels of anxiety and emotional inhibition (Perrine, 1996). For
these effects, MDA has been used during psychotherapy to help
facilitate the expression and integration of meaningful,
disturbing emotional content that a patient might be chronically
experiencing and dwelling upon (e.g., Naranjo, 1973; Stolaroff,
1997; Yensen, et al., 1976). Andrew Weil has also reported an
increase in muscular coordination with MDA: "I have also tried
things like rock climbing and swimming after taking MDA and
again find that my body works in a more coordinated, smoother
fashion and that I can do things with it that I usually cannot,"
(Weil, 1976: pg. 335). Also, in contrast to LSD which seems to
'demand' inner exploration, MDA has been reported to be more
gentle in 'inviting' introspection (Yensen, et al., 1976).

MDMA, which didn't become very well-known until the early
1970s, was actually first synthesized some time during 1912. The
pharmaceutical firm E. Merck applied for a patent on the
compound on December 24th, 1912 and was issued that patent on
May 16th, 1914 (though the patent has since expired making the
compound public domain) in Darmstadt, Germany (Shulgin, 1986).
There is a common myth sometimes heard that MDMA was first
patented as an appetite suppressant, but this rumor is
completely false. MDMA was synthesized during an investigation
of precursors to be used in making other compounds (Cohen,
1998).

MDMA seems to have remained in relative obscurity until
the 1950s, when it was investigated by the U.S. Army as Edgewood
Arsenal experimental agent 1475 (EA-1475), most likely as a
potential 'truth-serum' (Cohen, 1998). There is also a reference
to its synthesis being investigated in Poland in 1960 (Shulgin,
1986), and Alexander Shulgin himself did synthesize it in 1965
while working at Dow Pharmaceuticals, but he had never tried
consuming it (Shulgin & Shulgin, 1992).

It wasn't until 1967 or 1968 when Alexander Shulgin met
Merrie Kleinman, a young chemistry graduate student at the
University of California - San Francisco, that his interest in
MDMA was renewed. She told him that she had synthesized some of
the N-methylated MDA, and with two close friends had tried it
(Perrine, 1996). She and her friends each having ingested 100 mg
of MDMA, Merrie said of the experience only that it was quite
emotional but overall left them with a good feeling. Shulgin
then synthesized it again himself and ingested some, finding it
"unlike anything I had taken before," (Shulgin & Shulgin, 1992).

Alexander Shulgin's synthesis of MDMA at the end of the
1960s marks the introduction of this compound into the circles
of psychotherapists and researchers he knew interested in
exploring the hidden recesses of the mind. This time marked the
introduction of MDMA onto the street as well, though it did not
gain its massive popularity of today until perhaps 1980. By the
mid-1970s however, MDMA-assisted psychotherapy had become very
popular, as it had not yet been scheduled (unlike MDA, which was
included in the Controlled Substances Act of 1970) and had
produced amazing results in therapy sessions (Cohen, 1998). The
primary benefits with which MDMA is attributed include: having
little psychological risk (compared to LSD), effects lasting
only 3 to 5 hours (again, compared to LSD's 6-10 hours),
enhanced bonding and communication between the therapist and the
patient or between the two partners of a couple, facilitation of
the expression of emotions and opinions, and little or no
perceptual or cognitive distortions or loss of ego control
(again, in contrast to LSD) (Greer, 1985; see also Greer and
Tolbert, 1986, 1998; Liester, et al., 1992; Nichols, 1986;
Stolaroff, 1997; Downing, 1986).

The effects and chemistry of MDMA (and MDA) are in fact so
different than typical hallucinogens that they are deserving of
their own name as a qualitative class of compounds. The case for
this is quite thoroughly and convincingly made by David Nichols
(1986), who gives several arguments for the new class name of
'entactogens'. "First of all, MDA itself [and MDMA] is really a
unique compound among the so-called hallucinogens. It is not
generally used for its hallucinogenic effect, but rather for its
affect-enhancing qualities," (Nichols, 1986: pg. 306). Secondly,
all other hallucinogenic amphetamines (e.g., the substituted
amphetamine DOM) are active only in their levo-, or R-(-),
optical isomer while MDMA is active in its dextro-, or S-(+),
optical isomer, and MDA is active in both forms though with
differing effects in each. Thus, MDMA and MDA cannot be acting
at exactly the same site of action in the brain as other
hallucinogenic amphetamines, because a "structurally well
defined receptor does not suddenly decide to accept the dextro-
isomer for one compound, when for all other members of a drug
series [(i.e., the substituted amphetamines)] it prefers the
levo-isomer," (Nichols, 1986: pg. 307). It is energetically
impossible due to bonding constraints at the molecular level.

Finally, it is well-known that in all other hallucinogenic
substituted amphetamines, if you change the alpha-methyl group
to an alpha-ethyl group, you lose all hallucinogenic activity
(most likely because the molecule no longer fits the receptor).
To test this out in MDMA, Nichols and his research team
substituted an alpha-ethyl group for the alpha-methyl group on
MDMA and the resulting compound was N-methyl-1-(1,3-benzodioxol-
5-yl)-2-butanamine, or MBDB. If this compound followed the trend
of all other hallucinogenic substituted amphetamines, then it
would be expected to lose all hallucinogenic activity. When
tested in both humans and rats, however, this was not the case.
MBDB did have effects in humans and rats similar to MDMA, though
less potent, and also the active form was the dextro- isomer as
with MDA and MDMA (Nichols, 1986).

Because of these three key pieces of evidence, Nichols and
his team felt a new term was needed for this chemical class of
compounds. Rejecting empathogen as too limiting and also
suggesting deleterious effects (i.e., "pathogen"), they came up
with the term entactogen. In Nichols' words: "It seemed that the
effect of these drugs was to enable the therapist - or patient
to reach inside and deal with painful emotional issues that are
not ordinarily accessible. Just as the word 'tact' has the
connotation of communicating information in a sensitive and
careful way, so as to avoid offense, it seemed that the Latin
root of this word, tactus, would be appropriate as part of the
term. Addition of the Greek roots en (within or inside) and gen
(to produce) created the term 'entactogen', having the
connotation of producing a touching within," (Nichols, 1986: pg.
308).

By the mid-1980s, while still prospering as a
psychotherapeutic agent, MDMA had caught-on in the dance-club
scene, especially in Texas. "What had been a low-level
production from chemists in the Boston area was superseded when
one of their Southwest distributors started his own operation in
Texas, and renamed the drug 'Ecstasy,'" (Perrine, 1996: pg.
304). It became so available in Texas bars and nightclubs at one
point, that supposedly some establishments even allowed
purchases by credit-card and sometimes even handed it out as a
free promotional item (Cohen, 1998). 1984, however, was the
beginning of the end when Lloyd Bentsen, a Texas Senator, made
the first request to the DEA to schedule MDMA.

This action sparked off two years of heated debate about
whether or not to place MDMA in Schedule I, with both sides
emphatic in their beliefs. A crucial piece of evidence used by
the DEA, though resting on the misinformation of MDMA being
synonymous with MDA, was a paper published in Science in 1985 by
George Ricaurte and his team (i.e., Ricaurte, et al., 1985). The
data of this paper indicated that a 10 mg/kg dosage of MDA
(equivalent to a 500-1000 mg dose in humans) caused a reduction
in serotonin levels in the rat forebrain. Although, ironically,
one of the conclusions made by the authors was that "the doses
of MDA typically ingested by humans may not be sufficiently high
to induce serotonin neurotoxicity, unless humans are more
sensitive than rats to the toxic effects of MDA," (Ricaurte, et
al., 1985: pg. 988). After evven more court hearings, MDMA was
eventually placed in Schedule I, temporarily in July of 1985,
and permanently on November 13, 1986 (Cohen, 1998). On December
22nd, 1987, it was temporarily placed in Schedule III (accepted
medical use but moderate potential for abuse and physical and/or
psychological dependency) due to subsequent court hearings and a
decision that there were indeed acceptable medical uses for
MDMA, but unfortunately this decision was reversed and on March
23rd, 1988 it was placed back in Schedule I (Liester, et al.,
1992).

Not much changed in any positive way with the scheduling
of MDMA, in my opinion. Effectively, these were the real
consequences: the price on the street soared to $20-$25 per
tablet or capsule; the quality, puurity and exact amount of MDMA
in each capsule or tablet became even more uncertain; previously
legal psychotherapy was forced underground; the criminal element
of the 'black market' brought a new factor of potential
violence, inherent in such illegal dealings involving large sums
of money, to all levels of MDMA manufacture, distribution and,
now, smuggling of both product and precursors; and lastly, the
consumption of MDMA seems to have went up, not down, since 1985
with the massive popularization oof the drug (now known as 'E',
'X' and 'XTC') in the underground dance-club, or 'rave', scene
which emerged in the United States and England in the mid-1980s.

Despite the usual governmental propaganda, perhaps we
should examine the real risks involved in MDMA use. It seems, at
least psychologically, extremely safe especially when compared
to most legally-prescribed drugs: "... in 1986, J. Newmeyer
conducted a review showing that adverse reactions to MDMA
averaged fewer than 20 per year from all emergency rooms
nationwide, despite literally millions of individuals using the
drug," (Perrine, 1996: pg. 304). A very real risk, however,
which is associated with MDMA use in the rave-scene, is the
danger of heat-exhaustion when dancing for hours on end without
drinking any water or juice, especially when the venue is
indoors and over-crowded. Heat-exhaustion and hyperthermia have
caused many casualties and even fatalities associated with,
though not caused by, MDMA use.

The neurotoxicity of MDMA however, remains somewhat
unclear, though if there is any at all it seems to be no more
than that caused by such prescription drugs as Fenfluramine, a
Schedule IV drug used to treat obesity (e.g., see Frederick, et
al., 1998 and McCann & Ricaurte, 1995). The glaringly obvious
difference which automatically appears here, however, is that
while Fenfluramine (which has been used by over 50 million
patients) is taken daily for sometimes many consecutive months,
a dose of MDMA used in psychotherapy may be given only once or
twice a year, if that. Even McCann and Ricaurte (proponents of
MDMA neurotoxicity) have said, "Although it is not clear why the
potential for serotonin neurotoxicity in humans receiving
Fenfluramine has not received much attention, it may be, in
part, related to its use in a more socially acceptable
therapeutic setting," (McCann & Ricaurte, 1995).

Regarding the actual neurotoxicity caused by both MDMA and
Fenfluramine in animals (not humans), they have both been found
in monkeys and rats to deplete serotonin levels as measured by
reduced levels of 5-hydroxyindoleacetic acid (5-HIAA), a
metabolite of serotonin, in the cerebral spinal fluid (CSF)
(e.g., Ricaurte, et al., 1988a; Steele, et al., 1994; Hegadoren,
et al., 1995; Fischer, et al., 1995; McCann, et al.,
1996),reduced levels of serotonin as measured directly (e.g.,
Ricaurte, et al., 1988b), and increased locomotor activity
(Nagilla, et al., 1998). The reduced serotonin levels seem to be
due to changes in serotonergicc neurons, specifically at pre-
synaptic serotonin uptake sites (Sprague, et al., 1998). Even
though these studies with high dosages and/or repeated
administrations of MDMA have shown some serotonin depletion in
animals, a 1993 primate study was conducted by George Ricaurte
that unfortunately was never published indicating that a single
experimental/therapeutic dose MDMA was probably not neurotoxic
at all. In an October, 1999 letter to Neuropsychopharmacology,
Franz X. Vollenweider, et al., state: "Finally, 2.5 mg/kg MDMA
given p.o. once every 2 weeks for 4 months did not alter 5-HT
and 5-HIAA brain content in squirrel monkeys (Ricaurte 1993,
pers. comm. to the Swiss Federal Ethical Committee),"
(Vollenweider, et al., 1999: pg. 599).

There are several problems with neurotoxicological studies
being generalized to humans occasionally using a therapeutic
dose of MDMA in a clinical setting. First, the dosages used in
rats and monkeys have been anywhere from 20-80 mg/kg, sometimes
administered subcutaneously, intramuscularly or
intraperitoneally (i.e., without a 'first pass' through the
stomach and liver) (Hegadoren, et al., 1999). Also, 20-80 mg/kg
in a 50-100 kg (110- 220 lb) human equals 1000-80,000mg of MDMA
consumed, and in these studies this dosage was sometimes given
repeatedly in one day or over a few days to elicit the reported
neurotoxicity. These dosages are quite high, to say the least,
given the normal therapeutic dose of 50-250 mg. Another problem,
perhaps supporting the strongest case against the neurotoxicity
data, is that generalizing findings across species is by itself
inconclusive. Dan Perrine (1996) points out that "while
serotonin neurodamage in monkeys from MDMA appears to be
permanent, in rats function seems slowly to return to normal,"
(pg. 305). So presently, the debate still rages on as to whether
MDMA cause neurotoxicity or not. It does seem tragic however,
that because of its Schedule I status, the research which needs
to be done on MDMA to show its probable harmlessness and
already-proven clinical efficacy has been severely hampered
while drugs such as Fenfluramine continue to be prescribed on a
regular basis.